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Science. 2014 Oct 3;346(6205):1255784. doi: 10.1126/science.1255784. Epub 2014 Oct 2.

Tracking cancer drugs in living cells by thermal profiling of the proteome.

Author information

1
Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany. mikhail.m.savitski@gsk.com marcus.x.bantscheff@gsk.com gerard.c.drewes@gsk.com.
2
Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany.
3
Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4
Department of Proteomics and Bioanalytics, Technische Universit√§t M√ľnchen, Emil Erlenmeyer Forum 5, Freising, Germany. German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.
5
Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. Centre for Biomedical Structural Biology, Nanyang Technological University, Singapore.

Abstract

The thermal stability of proteins can be used to assess ligand binding in living cells. We have generalized this concept by determining the thermal profiles of more than 7000 proteins in human cells by means of mass spectrometry. Monitoring the effects of small-molecule ligands on the profiles delineated more than 50 targets for the kinase inhibitor staurosporine. We identified the heme biosynthesis enzyme ferrochelatase as a target of kinase inhibitors and suggest that its inhibition causes the phototoxicity observed with vemurafenib and alectinib. Thermal shifts were also observed for downstream effectors of drug treatment. In live cells, dasatinib induced shifts in BCR-ABL pathway proteins, including CRK/CRKL. Thermal proteome profiling provides an unbiased measure of drug-target engagement and facilitates identification of markers for drug efficacy and toxicity.

PMID:
25278616
DOI:
10.1126/science.1255784
[Indexed for MEDLINE]
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